Project Summary The goal of this proposal is to support the PI?s development into an independent patient-oriented researcher with expertise in common variable immunodeficiency (CVID) and B cell biology. The PI will be mentored in all aspects of the proposal and receive training in systems biology approaches to human immunology research. Candidate - The PI holds MD and PhD degrees, has completed internal medicine residency and allergy/immunology fellowship at Mount Sinai Medical Center, and has been appointed Assistant Professor in Department of Medicine at the Icahn School of Medicine at Mount Sinai. He has joined the laboratory of Dr. Charlotte Cunningham-Rundles and his preliminary work defined the immunological characteristics of CVID non-infectious complications. Elucidating pathogenesis of these complications is the focus of this proposal. Research ? CVID is the most common symptomatic primary immunodeficiency. Its greatest morbidity and mortality results from non-infectious complications, namely autoimmunity (AI) and lymphoid hyperplasia (LH). The PI has previously detailed the cellular characteristics of pulmonary LH underlying interstitial lung disease (ILD) in these patients and defined clinical and laboratory associations of these complications. Recently, the PI found B cell activating factor (BAFF) elevated in the CVID patients with progressive AI and LH and the cytokine to be produced locally in the lungs of patients with ILD. Also, BAFF receptor (BAFF-R) expression and signaling is localized to follicles within LH, B cell maturation is most profoundly arrested in CVID patients with AI and LH, and apoptosis resistance of the persisting immature B cell subsets is mediated by BAFF. We hypothesize that AI and LH result from excessive BAFF-R signaling in immature B cell subsets in CVID. Career Development - The primary mentor (Dr. Cunningham-Rundles) is the David S. Gottesman Professor of Immunology at Mount Sinai and is an international authority on CVID. She runs the NIH-funded lab in which the PI will be based and directs the large clinical immunology practice from which study subjects will be recruited. Co-mentor Dr. Andrea Cerutti is an expert in T cell-independent activation of B cells via cytokines such as BAFF and is a Professor of Medicine at Mount Sinai. Additional advisory committee members are respected investigators with diverse expertise that will supplement the candidate?s research mentorship and career development. The candidate will also benefit from the collaborative research environment of the Icahn School of Medicine at Mount Sinai and complete coursework in bioinformatics and systems biology. Synopsis ? Drawing upon a focused research approach, expert mentorship, and a strategic educational plan, this proposal details a 5 year training program for an academic career in primary immunodeficiency and human B cell biology. At the conclusion of training, the PI will be positioned to become an independent physician scientist with expertise in CVID, BAFF biology, and high throughput human immunology research methods.